Respiratory rectification

ABSTRACT

A means for treating breathing disorders by stimulating respiratory muscles or nerves to entrain respiratory systems while leaving respiratory drive intact. Embodiments of the invention employ frequency analysis to determine if appropriate stimulation energy is being applied.

SUMMARY

In humans, gas exchange is accomplished by rhythmic inflation anddeflation of lungs. During ventilatory movements, the lung is passiveand its volume is determined by the size of the thorax, which in turn isdependent mainly on the activity of the intercostal muscles and thediaphragm.

Vertical movement of diaphragm is about 1.5 cm during quiet breathingand may go up to 7 cm in deep breathing. A descent of the diaphragm by 1cm will increase the thoracic capacity by approximately 300 mL and causea corresponding volume of air to enter the lungs. Thus, the movements ofthe diaphragm may be responsible for about 60-80% of lung distention andthe total air breathed.

A respiratory control center in the brain controls respiratory muscles.Respiratory muscles consist of the respiratory pump (diaphragm andintercostal muscles) and airway muscles. Neural signals that travel tothe respiratory muscles constitute the central respiratory drive. Whilethe diaphragm is the main source of power for the respiratory pump, thefunction of airway muscles is to keep the airway open. Without centralneural drive the airway may collapse or partially occlude.

During sleep the respiratory control is unconscious and governed bymetabolic demand (mainly the need to remove CO2 from blood). In allhumans, the central neural drive to the respiratory pump and airwaymuscles during sleep is reduced compared to an awake state. In thepresence of a mild pathology, airway resistance to airflow can beincreased during sleep resulting in, for example, snoring. In extremecases the airway can close completely resulting in obstructive sleepapnea (OSA). In some cases deregulation of the central control canresult in periodic breathing and severe disease that can damage multipleorgans.

Central Sleep Apnea (CSA) is a form of periodic breathing characterizedby an oscillating central respiratory drive. CSA may be characterized bya typical waxing and waning respiratory pattern made up of alternatingapneas and hyperpneas (periods of hyperventilation), historically calledCheyne Stokes Respiration (CSR).

Obstructive Sleep Apnea (OSA) is characterized by upper airwayinstability. A collapsed airway prevents or reduces inspiration in theface of continuing or increasing respiratory effort. A common pattern ofOSA in the general population is characterized by periodic arousals thatresult in abrupt opening of the airway.

Inventors have discovered that in some patient populations, such asthose with congestive heart failure (CHF) for example, it is difficultif not impossible to separate the underlying mechanisms of OSA and CSA.A purely central CSR pattern is somewhat rare. Common presentation ofperiodic breathing in CHF patients may consist of alternatingrespiratory events that can include hyperpneas, hypopneas, and central,obstructive and mixed apneas. A significant overlap exists, and mostpatients experience varying degrees of both central and obstructiveevents. Indeed, it is believed that oscillating central respiratorydrive may lead to upper airway closure or increased resistance.

Following an extensive series of experiments, inventors realized thateffective treatment of many cases of periodic breathing requiredaddressing central neural drive to breathe as well as airway issues.Because of the relationship between respiratory pump muscles and airwaymuscles, inventors desired to modulate the brain's intrinsic respiratoryactivity to affect both aspects of respiration. The brain's respiratorycontrol center is located in the medulla of the brain and is notdirectly accessible for modern neuromodulation technologies. Theinventors were therefore compelled to investigate neural inputs to thebrain that govern the behavior of the respiratory control center.

The brain's respiratory control center receives inputs fromchemoreceptors in the arterial vasculature (in the aortic arch, carotidbodies and blood vessels in the brain itself) and from mechanoreceptorssuch as the respiratory pump muscles, pulmonary stretch receptors in thelung, and intercostal stretch receptors. It is known that altering inputinto the brain from chemoreceptors by making the patient breathe in somecarbon dioxide can control periodic breathing.

Phrenic nerves control the motion of the diaphragm, which in turn canlead to activation of series of neural inputs to the brain, for exampleby stretching various innervated tissues in the thorax. TheHering-Breuer reflex is a powerful neural feedback from the lung stretchreceptors to the brain. When the lung is inflated and stretched, therespiratory center of the brain suspends the respiratory drive. It isbelieved that entrainment of respiration to external stimulus insleeping humans involves the Hering-Breuer reflex as well as otherneural inputs.

The technology inventors chose for investigation was phrenic nervestimulation. One form of phrenic nerve stimulation known as“electrophrenic ventilation” or “diaphragmic pacing” has been used formany years to replace intrinsic breathing. The physiology of respiratorypacing is straightforward. The phrenic nerve is stimulated to take overrespiration by slightly hyperventilating the patient. The consequentreduction of blood carbon dioxide concentration is sensed by the brain'srespiratory control center and substantially all the neural output fromthe center (central respiratory drive) stops. A patient, thus paced, maynot experience respiratory disturbances while paced but becomestemporarily dependant on phrenic “pacing” for ventilation and gasexchange.

Such phrenic pacing was used to treat Paraplegics and Central CongenitalHypoventilation Syndrome in children since the 1960s and successfullyprevented death by replacing natural respiration drive with artificialone. By taking over breathing, such pacing suppresses intrinsic centralrespiratory drive. While eliminating oscillations of respiratory driveit also may eliminate the drive to keep the airway open. In patientswith Central Congenital Hypoventilation Syndrome this limitation can beovercome by tracheostomy (a surgical procedure on the neck to open adirect airway through an incision in the trachea). A tracheostomy isunacceptable in patients with periodic breathing.

By contrast, embodiments in accordance with the invention applystimulation to only one phrenic nerve at a constant rate that is in someembodiments slightly below the patient's intrinsic rate. Theseembodiments may result in the entrainment of the patient's centralrespiratory activity rather than suppression of the intrinsic drive.When applied during periodic breathing in sleeping individuals, anddelivered within a particular range of stimulation parameters, this formof phrenic nerve stimulation often resulted in the restoration of normalbreathing rhythm, was sustainable, and was well tolerated during naturalsleep.

In some embodiments in accordance with the invention, stimulationresults in rhythmic contractions of one hemi-diaphragm innervated by thestimulated nerve and consequent rhythmic lung inflations. The patient'sintrinsic breathing rhythm is modulated by stimulation, becoming moreregular and exhibiting less periodicity. The improvement in breathing isbelieved to be achieved by the mechanism of lung distension andentrainment of the neurons in the brain respiratory center, among othermechanisms, rather than by control of breathing per se. Spontaneousbreathing and central respiratory drive are preferably preserved, thusresulting in the benefit of maintained airway muscle tone and naturalblood gas regulation.

Another embodiment in accordance with the invention concerns monitoringand controlling diaphragmatic stimulation and entrainment ofstimulation. This embodiment is based on the assumption that whenstimulation entrains respiration, the spectral power of the respiratorysignal in the immediate range of the driving frequency will besignificantly higher than in other frequency bands. In one embodiment aratio of total variance of respiration signal that falls into the narrowband centered on the stimulation frequency to the total variance in thebroader respiratory frequency band can be calculated. It can be expectedthat the value of this ratio will increase proportionally to theentrainment of respiration by stimulation, thus enabling guided andcalibrated therapy based on the effect of stimulation on actualrespiration. Two exemplary calculation methods are disclosed herein forsuch a ratio: the spectrum method and the histogram method. It is to beunderstood that these methods are not the only ways to determineentrainment or nerve or muscle capture efficacy by frequency analysis,and other methods will occur to those of skill in the art upon readingthis disclosure.

Inventors observe occasional regularization of breathing rhythm andresolution of both central and obstructive apnea during unilateralphrenic stimulation. Inventors saw that the phrenic stimulation preventsand corrects the intrinsic periodicity of breathing in patients thatfrequently exhibit oscillatory respiration during sleep. Inventorsobserve that the patient's breathing, previously highly irregular,gradually becomes tuned to the rhythm of phrenic stimulation and followsit if the rate of stimulation was changed. Inventors have also observedfixed and repetitive coupling between the external stimulus and neuralinspiratory activity in the respiratory control center of the brain.Inventors confirmed that the patient breathing was entrained, and indeedspontaneous, by making the following observations:

-   -   (1) When stimulation was abruptly stopped the patient did not        stop breathing. In some cases patients continued breathing “as        if still stimulated” following the no-longer-present cues for        several minutes before reverting back to the pre-stimulation        pattern.    -   (2) Because only one phrenic nerve was stimulated, the second        lung was free to inflate and deflate without the direct        influence of stimulation. Inventors confirmed the independent        motion of the un-stimulated lung by separate transthoracic        impedance measurements.    -   (3) Frequently, patients were observed to insert or interlace        spontaneous small breaths in between breaths entrained to the        stimulation, thus confirming that the central respiratory drive        remained active. These interlaced breaths did not interfere with        the pattern of entraining.

It is believed that stabilization of blood gases and the elimination orreduction of intermittent hypoxia and arousals associated withhyperventilation through entrainment with phrenic stimulation improvesairway tone. Hypoxia in an exceptionally strong stimulus tohyperventilate, as is the neurologic arousal that often follows hypoxia.The severity of hyperventilation that follows the intermittent hypoxiadetermines the subsequent reduction of blood CO2 that results in thewithdrawal of the neural stimulus to both respiratory pump muscles andthe airway muscles. The inverse is also true. The reduction of hypoxiaand the subsequent hypoxia-exacerbated hyperventilation should helpsustain respiratory drive and maintain neural muscle tone of the airwayafter the transient hyperpnea is over.

Another way in which the CSA is thought to reduce upper airway stabilityand induce OSA is by promoting periods of hypopnea. During hypopnea, theactivity of both respiratory pump muscles (e.g. diaphragm) and upperairway dilator muscles (e.g. genioglossus) is reduced. Therefore, awaxing-waning pattern of central respiratory drive in an individualhaving an upper airway prone to collapse may result in to obstructiveapnea/hypopnea during the periods of hypopnea because of upper airwayhypotonia (low muscle tone). It is reasonable to assume that theopposite is also true. Reducing hypopnea in CSA patients will helpstabilize the airway by increasing airway muscle tone.

In the context of this disclosure, hypopnea broadly refers to atransient reduction of airflow (while asleep) that lasts for at least 10seconds because of transient shallow breathing, or an abnormally lowrespiratory rate. In medical literature breathing that is too shallow(hypopnea) or too slow (bradypnea) is sometimes differentiated. Hypopneais less severe than apnea (which is a more complete loss of airflow) butcan likewise result in a decreased amount of air movement into the lungsand can cause oxygen levels in the blood to drop (hypoventilation).

There is no firm scientific consensus on the narrow or quantitativedefinition of hypopnea and it is understood that many definitions areoften used in scientific literature and can be applied.

For example in their research, which served as a basis for thisdisclosure, inventors used transient reduction of respiration (airflow)by >30% for the duration of 10 to 60 seconds accompanied by detectable(4%) oxygen desaturation as the quantitative “technical” definition ofhypopnea. Within the narrow scope of this quantitative definition,hypopnea and transient hypoventilation are for all practical purposeequivalents.

When defined broadly hypoventilation is the state in which a reducedamount of air enters the alveoli in the lungs, resulting in decreasedlevels of oxygen and/or increased levels of carbon dioxide in the blood.Hypoventilation can also be defined broadly, and perhaps better, asbreathing that is not adequate to meet the needs of the body.Hypoventilation can be due to hypopnea or to diminished lung function.Hypoventilation can be transient (as a result of hypopnea) or sustaineddue to various pathologies such as in congenital disease, ChronicObstructive Pulmonary Disease (COPD) or obesity.

Periodic lung inflations play an important role in the maintenance ofneural sympathetic-parasympathetic balance, heart rhythm and bloodpressure regulation. As early as in the 1940s many of these physiologicinteractions were traced to neural feedbacks that signal lung expansionto the autonomic nervous system. The role of the autonomic nervoussystem in the body's homeostasis is particularly important during sleep.These beneficial feedbacks have been graded according to lung inflation.

The importance of neural feedbacks from the stretch receptors in thelungs to the multiple brain centers that control cardiovascular activitymay be best demonstrated by so called Respiratory sinus arrhythmia.Respiratory sinus arrhythmia (RSA) is a heart rate change that occurs insynchrony with respiration, by which the R-R interval on an ECG isshortened during inspiration and prolonged during expiration. AlthoughRSA has been used as an index of cardiac vagal function, it is also aphysiologic phenomenon reflecting respiratory-circulatory interactionsuniversally observed among vertebrates. Studies have shown that theefficiency of pulmonary gas exchange is improved by RSA, suggesting thatRSA may play an active physiologic role. The matched timing of alveolarventilation and its perfusion with RSA within each respiratory cyclecould reduce energy expenditure by suppressing unnecessary heartbeatsduring expiration and ineffective ventilation during the ebb ofperfusion. RSA or heart rate variability in synchrony with respirationis a biological phenomenon, which may have a positive influence on gasexchange at the level of the lung via efficient ventilation/perfusionmatching.

Inventors observed increase of RSA when patients with CHF were treatedin accordance with embodiments of the invention. It is reasonable toexpect that other benefits such as dilation of blood vessels andreduction of malignant arrhythmias will follow.

Phrenic or diaphragm stimulation in accordance with embodiments of theinvention can expand the breath or lung volume to combat the effects ofhypopnea. Stimulation is also expected to result in sustained lungexpansions as opposed to the waxing and waning pattern found in CSA.Additional airway tone benefit can be expected from these improvements.In patients with significant CSA, upper airway collapse and resultingOSA may be secondary to the withdrawal of neural and mechanical stimulusto the airway caused by reduced parasympathetic activation anddiminished lung inflation during central apnea/hypopnea episodes.

Clinical benefit can be derived from the entrainment of the intrinsicrespiratory rhythm by stimulation. Increased lung volume, stabilizedblood gas composition and reduced hypoventilation all suggestimprovement of airway dynamics in addition to the primary correction ofcentral respiratory instability.

Upper airway dilator muscles play an important role in maintainingairway patency. Many of the pharyngeal dilator muscles are known todemonstrate inspiratory phasic activity, the onset of which precedesdiaphragmatic activity. That is, the airway muscles contract in phasewith respiration slightly prior to the respiratory pump muscles, thus“preparing” the pharyngeal airway for the development of negativepressure during inspiration.

The best studied pharyngeal muscle is the genioglossus. The genioglossusreceives input from the brain respiratory control center (or moreprecisely from the brainstem respiratory central pattern generator)located in the medulla. The hypoglossal nerve activates thegenioglossus, and the hypoglossal nerve has been detected firing 50-100ms prior to the phrenic nerve in healthy patients.

Chemoreceptive inputs are also important in influencing hypoglossalmotor nerve output. Low blood CO2 (hypocapnea) reduces activation andhigh CO2 (hypercapnea) increases it. Thus it may be useful for anyperiodic breathing treatment to avoid hypocapnea and the reduced airwaymuscle activation that accompanies hypocapnea.

Embodiments in accordance with the invention are usable to treatperiodic breathing in sleeping patients, but they can also be used toregularize breathing in resting people with ischemic heart disease,heart failure, hypertension, COPD, and other conditions where improvedbreathing efficacy is advantageous.

In one embodiment in accordance with the invention, a measured frequencyzone is defined based on measured physiological signals associated withthe intrinsic contraction of a muscle. A stimulation frequency zone isdefined based on stimulation frequency of an electrical pulse generatorconfigured to stimulate the muscle or a nerve associated with the muscleat a different frequency than the intrinsic frequency. The muscle or anerve associated with the muscle is stimulated, and the impact ofstimulation is determined by comparing the measured power of an array ofsignals that fall within the measured frequency zone to the measuredpower of the array of signals that fall within the stimulation frequencyzone. In variations of this embodiment, the physiological signal is asignal representative of respiration. In another embodiment, the muscleis a diaphragm muscle. In yet another embodiment, the measured frequencyzone comprises a range of frequencies proximate the respirationfrequency of a patient.

In another embodiment in accordance with the invention, a system forelectrical stimulation of a nerve or muscle includes an electrical pulsegenerator that delivers energy to stimulate a muscle at a firstfrequency, the first frequency different from a second frequency atwhich the muscle intrinsically contracts. The system of this embodimentalso has a sensor that senses physiologic activity indicative ofcontraction of the stimulated muscle and an electronic memory to storean array of data generated by the sensor over a period of time. Afrequency analyzer analyzes the array of data to determine the powerdistribution across a frequency band for the sensed physiologic activityand circuitry of the system is capable of comparing the power in a bandproximate the stimulation frequency to the total power across thefrequency band for the sensed physiologic activity.

In another embodiment in accordance with the invention, a system forelectrical stimulation of a nerve or muscle includes an electrical pulsegenerator that delivers energy to stimulate a muscle at a firstfrequency, the first frequency different from a second frequency atwhich the muscle intrinsically contracts. The system of this embodimentalso has a sensor that senses physiologic activity indicative ofcontraction of the stimulated muscle and an electronic memory to storean array of data generated by the sensor over a period of time. Afrequency analyzer analyzes the array of data to determine the powerdistribution across a frequency band for the sensed physiologic activityand circuitry of the system is capable of comparing the power in a bandproximate the stimulation frequency to the total power across thefrequency band for the sensed physiologic activity. In this embodiment,the circuitry is capable of increasing the energy delivered by the pulsegenerator if the ratio of the power in the band proximate thestimulation frequency to the total power is below a threshold.

In another embodiment in accordance with the invention, a system fortreating disordered breathing includes an electrical pulse generatorcapable of providing electrical stimulation signals to a phrenic nerveor diaphragm of a patient at a predetermined signal frequency. Thisembodiment has a respiration sensor capable of sensing a signalrepresentative of the patient's respiration and a frequency comparatorthat compares the power density of the frequency distribution of sensedrespiration signals over a stimulation frequency band to the powerdensity of sensed respiration signals over a respiratory frequency bandThe system includes power adjusting circuitry that adjusts the power ofthe electrical stimulation signals provided by the electrical pulsegeneration based on the comparison of the power densities. In variousembodiments, the power adjusting circuitry could adjust stimulationcurrent, stimulation voltage. The frequency of the pulses in a pulsetrain, a pulse duration of the pulses in a pulse train, or otherparameters.

In yet another embodiment in accordance with the invention, a phrenicnerve or diaphragm is stimulated at a frequency below an intrinsicbreathing rate. The stimulation is delivered at an intensity sufficientto entrain respiration while leaving intrinsic drive to breathe intact.In some embodiments, respiratory drive is manifested as 2:1 entrainment,in others as spontaneous breathing of an unstimulated lung, in others asminor breaths interlaced among entrained breaths, and in others asperiodic activation of airway muscles.

In another embodiment in accordance with the invention, disorderedbreathing is treated by detecting a signal representative of therespiration of a patient and conducting a frequency analysis of thesignal representative of respiration over a range of frequenciesconsistent with respiration. This embodiment includes the steps ofdetermining an intrinsic breathing rate or frequency and stimulating onehemidiaphragm of the patient at a frequency different from the intrinsicbreathing frequency. In this embodiment a frequency analysis of therespiration signal during stimulation is conducted. A capture index isdetermined by dividing the power distribution in a frequency rangeproximate the stimulation frequency to the power of the range offrequencies consistent with respiration to determine a capture index.Stimulation parameters are modified based on the calculated captureindex. In some embodiments, the signal representative of respiration maybe transthoracic impedance. In some embodiments, the stimulationfrequency is lower than the intrinsic breathing frequency.

In another embodiment in accordance with the invention, disorderedbreathing is treated by detecting a signal representative of therespiration of a patient and conducting a frequency analysis of thesignal representative of respiration over a range of frequenciesconsistent with respiration. This embodiment includes the steps ofdetermining an intrinsic breathing rate or frequency and stimulating onehemidiaphragm of the patient at a frequency different from the intrinsicbreathing frequency. In this embodiment a frequency analysis of therespiration signal during stimulation is conducted. A capture index isdetermined by dividing the power distribution in a frequency rangeproximate the stimulation frequency to the power of the range offrequencies consistent with respiration to determine a capture index.Stimulation parameters are modified based on the calculated captureindex. In some embodiments the stimulation power is increased if thecapture index is below a certain threshold. In some embodiments thestimulation power is decreased if the capture index is above a certainthreshold.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a waveform of the respiration data of an untreated patient.

FIG. 2 is a waveform of the respiration of the patient of FIG. 1 duringtherapy in accordance with embodiments of the invention.

FIG. 3 is a spectral graph of the respiration data presented in FIG. 1.

FIG. 4 is a spectral graph of the respiration data presented in FIG. 2.

FIG. 5 is a graph of experimental data relating to disordered breathingin a patient treated in accordance with embodiments of the invention.

FIG. 6 is a waveform of the respiration and stimulation data associatedwith a patient therapy in accordance with embodiments of the invention.

FIG. 7 is a control flowchart in accordance with embodiments of theinvention.

FIG. 8 is a schematic view of a patient and therapy device in accordancewith embodiments of the invention.

DETAILED DESCRIPTION

FIG. 1 is a waveform of the respiration data of an untreated patient.The waveform represents 60 seconds of data acquired during the time whenthe patient was asleep. Trace 101 represents normal breathing (at rest)for this patient. The trace 101 was acquired at 10:42 pm just before thepatient received therapy. The trace 101 represents airflow in and out ofthe patient lungs monitored with a flow meter (thermal sensor). At thistime patient does not show periodic breathing or apneas and the patientis breathing regularly at 24 breaths per minute (0.4 Hz).

FIG. 2 is a waveform of the respiration of the patient of FIG. 1 duringtherapy in accordance with embodiments of the invention. This waveformalso represents 60 seconds of data acquired when the patient was asleep.The patient has CSA and was treated using transvenous stimulation of theright phrenic nerve. Trace 103 represents stimulation pulse trains. Thestimulation pulse trains were applied at a constant rate of 18 perminute (0.3 Hz pulse rate), in this case below the patient's nativebreathing rate of 24 breaths per minute. Each pulse train is 1.67seconds long. During the pulse train application, the right phrenicnerve was stimulated and the right hemi-diaphragm muscles contracted(stimulation phase 104). Each pulse train is followed by the relaxationphase 105 that is also 1.67 seconds long in this example. During therelaxation phase the phrenic nerve is not stimulated. The stimulationpattern 103 represents therefore 50% duty cycle stimulation (50%inspiration-50% expiration). Other duty cycles or ratios can be used toachieve the objectives of the invention.

Each pulse train 104 is composed of series of individual pulses (notshown) supplied by a pulse generator. The pulse generator can beexternal or implanted. In this example the pulses are 150 μs(microseconds) long and are applied at a 20 Hz frequency. The pulsegenerator of this example applied pulses in a controlled pre-programmedfashion to reach a pre-programmed peak current amplitude of 4.9 mA. Toincrease patient's comfort, the electric current amplitude of pulseswithin the pulse train may be gradually increased, held constant andthen gradually decreased within the same pulse train. Other pulse trainshapes may be used to elicit desired contraction and relaxationresponses of the diaphragm muscle without deviating from the scope ofthis disclosure.

Trace 102 represents the respiration of the patient during thestimulation therapy. Similar to trace 101 from FIG. 1, it consists ofindividual breaths monitored by a flow meter. Each breath consists of aninspiration phase 106 and expiration phase 107. It can be noted thatthere are mostly large breaths 108 and some smaller breaths 109. Largebreaths are phase locked with stimulation pulses 103 and the patient'sbreathing can be said to be entrained to the stimulation. These largebreaths appear at the same rate as the stimulation pulse train rate of18 per min (0.3 Hz).

When only large breaths appear in series they indicate the 1:1entrainment (one breath for each stimulation pulse train). When smallbreaths appear, they may appear in a number of forms. In some cases,small breaths are interlaced between the large breaths at a rate thatcorresponds generally to the spontaneous breathing rate of 24 breathsper minute (0.4 Hz). In some cases, small breaths appear onlyoccasionally as metabolic demand requires. In other cases, periods ofinterlaced breaths correspond to 2:1 entrainment (two breaths for eachstimulation pulse train). In all cases the existence of smallspontaneous or 2:1 entrained breaths support the inference that whilebreathing is entrained in this fashion the respiratory control center isstill active

While breaths on the trace 102 appear at the same basic frequency as thestimulation 103, they are not necessarily exactly synchronized tostimulation. Inspiration 106 can start at a different delay timefollowing the start of stimulation pulse trains 104 and even can undercertain circumstances precede the onset of the corresponding stimulationpulse train.

In the embodiment represented in FIG. 2, stimulation is applied at therate somewhat lower than the spontaneous breathing rate at rest (in thisexample: 18 vs. 24/min). Stimulation may entrain spontaneous breathingbut does not replace it. Entrainment is evidenced by the variable timedelay and phase angle between the stimulation pulse trains and patientsinspiration effort. Additional evidence of entrainment is the periodicappearance of 2:1 and 1:1 entrainment or other small breaths that arenot entrained, which shows that respiratory drive is not suppressed, butentrained.

FIG. 3 is a spectral graph of the respiration data presented in FIG. 1.Periodic waveforms such as breathing waveforms illustrated by FIG. 1 canbe analyzed using various frequency domain methods, the most common ofwhich is spectral analysis.

FIG. 3 shows spectrum of normal spontaneous breathing of the patientillustrated by the trace 101 on FIG. 1. Such spectrum can be obtained byperforming Fast Fourier Transform (FFT) on 2-3 minutes of digitallyacquired respiratory signal data (in this example, airflow). Thespectrum can be a power spectrum, a power density spectrum or amagnitude spectrum. One can also think of the power spectrum as yieldingwhich frequencies contribute most to the variance of the signal. Thelarger the amplitude, the higher the variance. This is a meaningfulbroad definition of “power spectrum.” It is understood that manynumerical methods exist for calculating frequency distribution ofperiodic signals, and all are contemplated herein. The “spectrum” may becalculated for the range of natural respiratory frequencies thatgenerally are between 0 and 1.0 Hz. In the disclosed embodiment, thefrequency range of approximately 0.1 to 0.5 Hz was found. The selectedrange is designated “respiratory frequency band” (RFB) for the purposeof this disclosure. Other frequency ranges could be selected and theselection of this range is merely exemplary.

In FIG. 3 the RFB 204 is indicated by the square frame that includes allrespiratory frequencies important for the purpose of determiningentrainment effectiveness in this example. The fact that the patient'snatural respiration frequency peaks at 0.4 Hz 202 can be expected fromthe respiration trace 101 on FIG. 1. Another frequency band importantfor the determination of entrainment is designated “stimulationfrequency band” (SFB). It is represented by the narrow band square 203and in this case is centered on the frequency at which stimulation pulsetrains are applied as on trace 103 of FIG. 2.

The spectral graph of FIG. 3 corresponds to the period when stimulationtherapy is not applied. Power in the SFB band is low if the centralfrequency, in this case 0.3 Hz, is significantly different from thedominant respiratory frequency 202.

The effectiveness of respiratory entrainment can be determined bycomparing the spectral power in the SFB band to the total spectral poweror to the spectral power in other frequency bands, for example.Inventors have found it useful to designate a Capture Index (CI) as ameasure of therapy effectiveness. The capture index is calculated bydividing the spectral power in the SFB by the spectral power in the RFB.The capture index represents the fraction of total spectral plot ofrespiration that falls into the narrow band proximate the stimulationfrequency. It can be expected that the value of capture index willincrease proportionally with the entrainment of respiration bystimulation. The stimulation frequency thus becomes the dominantfrequency of the respiration signal as entrainment increases. There aremany numeric calculations that can be used to calculate capture index.For example, inventors used the following methodology, among others.

A spectral plot is a graphical technique for examining cyclic structurein the frequency domain. Strictly defined it is a smoothed Fouriertransform of the autocovariance function. The frequency is measured incycles per unit time. The spectral plot is displayed with a verticalaxis of smoothed variance (power) and a horizontal axis of frequency(cycles per observation).

The computations for generating the smoothed variances can be involvedand are not discussed further here. Spectral plots are a fundamentaltechnique in the frequency analysis of time series and are familiar tothose of skill in the art. Spectral plots may be used to determine howmany cyclic components there are in a cyclic waveform, whether or notthere is there is a dominant cycle frequency, and if so what is thedominant cycle frequency. For the purposes of this disclosure, thedegree of “domination” of the dominant (stimulation) frequency isrelated to the capture index.

In the example shown in FIG. 3, the CI was computed as: (Power in rangeof Stimulation Frequency+/−0.0183 Hz)/(Power from 0.1 to 0.5 Hz). Thewidth of the Numerator in this example is 0.0366 Hz. It is calculatedfrom the stimulation frequency value rounded to the nearest FFT “bin”with the Numerator width of 3 bins below and 3 bins above (6 binstotal). The resolution in the frequency domain in this example is 0.0061Hz/bin. This is termed the “bin width.” The choice of +/−3 bins was toaccount for some or the “bin spreading” that you see when thestimulation frequency is not an exact FFT bin frequency and for somenatural variance in the frequency of the entrained breathing. The FFTintervals are fixed by the data sampling rate (400 samples/sec) and theFFT length (216=65,636).

The data sample rate was 400 samples/sec. It is understood that other,lower sampling rates, for example 20 samples/second, may be moresuitable for embedded software calculations or other applications. Therecord length was 65,536 samples (this corresponds to 164.84 seconds).If lower data acquisition sampling rate is used, significantly fewersamples are needed but not likely less than, for example, 1,024 or2,048. Other record lengths, such as for example 2, 3 and 5 minutes werealso used successfully. In this example the capture index is calculatedas the ratio of the sum of the magnitudes of a frequency band±3 binswide (0.0366 Hz), centered around the known stimulation rate and the sumof the magnitudes (or power) from 0.1 to 0.5 Hz. Other window widths forboth the SFB and RFB could be used be used in different embodiments, andthe SFB need not be centered on the stimulation frequency. Common to allembodiments the “stimulation frequency band” SFB is narrower than the“respiratory frequency band” (RFB), such as for example<10% of RFB andincluded within the RFB.

FIG. 4 is a spectral graph of the respiration data presented in FIG. 2.Stimulation is turned on in this example and applied at the presetfrequency of 0.3 Hz as illustrated by the trace 103 on FIG. 2.

It can be seen that the respiratory signal (airflow) power spectrum peak302 is at the frequency 0.3 Hz that corresponds exactly to thestimulation frequency. Natural respiration power at 0.4 Hz is reflectedin a smaller peak 301. It is appreciated that the presence of thenatural respiration frequency power in the spectrum can vary dependingon the strength of stimulation and the patient's intrinsic respiratorydrive. The presence of noticeable respiratory activity at the naturalrespiratory frequency suggests that the respiratory drive is entrainedbut still active, i.e. not suppressed or dormant. Power in the SFB 303in this example represents larger fraction of RFB 304 than in theexample illustrated by FIG. 3. Therefore it can be expected that thecapture index (SFB/RFB) is also increased significantly. Indeedcalculation shows that the capture index increased in this example from0.24 (FIG. 3) to 0.46 (FIG. 4). Different calculation methods can resultin different numbers but the capture index is increased significantlywhen the patient's respiration is entrained.

FIG. 5 is a graph of experimental data relating to disordered breathingin a patient treated in accordance with embodiments of the invention.FIG. 5 illustrates the practical importance of capture indexing for thepurpose of restoring normal breathing in the setting of periodicbreathing. Severity of periodic breathing is commonly characterized byapnea hypopnea index (AHI). AHI is the total sum of respiratory events(apneas and hypopneas) that occur in one hour. AHI>15 is consideredsignificant and AHI>30 severe and very dangerous. There are knownstandard clinical methods of calculating AHI during sleep studies usingpolysomnography (PSG). PSG is a diagnostic test during which a number ofphysiologic variables are measured and recorded during sleep. The graphof FIG. 5 was obtained by investigators using PSG in a patient sufferingfrom serious periodic breathing while undergoing stimulation therapy inaccordance with embodiments of the invention. The patient's AHI isexpressed on the Y-axis as a function of capture index on the X-axis.During the experiment stimulation energy (in this case stimulationcurrent) was varied generating different levels of diaphragmicactivation and, as a result, different levels of entrainment. Captureindex was calculated later using a digitized record of the sleep studyand a methodology equivalent to those described in this disclosure.

It can be seen that during time periods when capture index was higherthe AHI was reduced. Stimulation resulting in capture indexes higherthan 0.5, as calculated in this example, practically eliminated periodicbreathing altogether.

It is understood that the use of FFT and the calculation of respiratoryspectrum is not the only way to implement the calculation of the captureindex. For example, the respiratory waveform can be processed andpresented as a series of numbers corresponding to breath lengths. Aseries representing the last 3-4 minutes of respiratory data canconsist, for example, of 60-80 breath lengths. A histogram of breathlengths can be than constructed that represents the frequencydistribution of breath lengths. If intrinsic respiration is entrained toa stimulation frequency, the frequency of occurrence of breath lengthscorresponding to the wavelength of that frequency will increase. Forexample if the stimulation frequency is 20/minute the breath length is 3seconds. As capture and entrainment increase, the breaths approximately3 seconds long will occur more and more frequently. To compensate forthe natural variability, breaths that are, for example, between 2.84 and3.18 seconds long can be included in the numerator of the capture indexcalculation. This range of breath lengths corresponds to the +/−0.0183Hz frequency band used in the spectrum based example described earlier.

The capture index in this method is computed as: (Sum of occupancies ofbreath lengths in range of Stimulation Frequency+/−selected band)/(Sumof occupancies of all breath lengths in the respiratory range). Therespiratory range of breath lengths can be for example from 2 to 10 sec.The 2 to 10 second breath length range corresponds to the 0.1 to 0.5 Hzrespiratory frequency.

The histogram based capture verification method is mathematicallydifferent from the spectrum based method, but similar in principle. Itis based on the assumption that when stimulation entrains respiration,breath lengths of the respiratory signal in the immediate range of thedriving frequency will be occurring with significantly higher frequencythan those in other respiratory frequency bands. Therefore the CaptureIndex is still calculated as the ratio of the variance of respirationsignal that falls into the narrow band centered on the stimulationfrequency to the total variance in the broader respiratory frequencyband. Inventors have demonstrated in patients that the value of captureindex calculated using the histogram method increased proportionally tothe entrainment of respiration by stimulation thus enabling guidedtherapy and correlated closely with the capture calculated using thespectrum method. It is appreciated that other methods of capture indexcalculation based on similar principle are possible and will occur tothose of skill in the art upon reading this disclosure.

FIG. 6 is a waveform of the respiration and stimulation data associatedwith a patient therapy in accordance with embodiments of the invention.The top trace 501 represents a patient's respiration (airflow). TheX-Axis represents 16 minutes of data record and the individual breathsare compressed compared to FIGS. 1 and 2 which showed only one minute ofdata. During this therapy period the stimulation energy (current) wasfirst gradually reduced and then turned off altogether. The bottom trace503 represents the stimulation electric current. During the first 3minutes the current was held constant at approximately 5 mA. Respiration501 was sufficiently entrained and periodic breathing was not present.During the period between 3 and 10 minutes of the recorded segment thecurrent 503 was gradually reduced. It can be seen that periodicbreathing is no longer controlled, and after 10 minutes alternatingapneas 504 and hyperpneas 503 indicating the typical pattern of periodicbreathing known as Cheyne-Stokes Respiration returns.

FIG. 7 is a control flowchart in accordance with embodiments of theinvention. FIG. 7 illustrates one potential method and algorithm thattakes advantage of capture indexing to implement and improve disorderedbreathing therapy. It is understood that the proposed capture indexmethodology has broad implications for respiratory therapies that usephrenic nerve or diaphragm stimulation and potentially for mechanicalventilation.

One embodiment in accordance with the invention employs a captureindex-type calculation embedded in an algorithm in a microprocessor ofan implantable pulse generator (IPG) that is capable of adjustingphrenic nerve stimulation energy in response to the calculated captureindex. The capture index can be calculated based on 2-3 minutes ofhistory of a respiratory signal, for example transthoracic impedance,and stimulation parameters can be automatically adjusted based on thecalculated capture index.

The embedded algorithm of this embodiment is capable of determining theintrinsic resting respiratory rate of the patient 601. This rate can be,for example, between 6 and 40 breaths/minute, but in one targetedpopulation of patients with periodic breathing it is likely between 12and 30 breaths/minute. The algorithm is capable of applying stimulationpulse trains to the patient's phrenic nerve at a set rate that in someembodiments is somewhat lower than the intrinsic rate 602. It can be,for example, 2-4 breaths lower than the intrinsic rate. Therefore if thepatient was determined by the algorithm to be breathing at 20 breathsper minute, the stimulation rate can be automatically set to 16 breathsper minute, for example. After sufficient respiratory signal informationis collected by the embedded software (this can be for example 3 minutesof data digitized at 20 samples per second) a capture index can becalculated 603.

Because physiologic conditions such as the patient's position, sleepstate, fatigue of the diaphragm and others may influence the response toentrainment, it can be expected that the capture index will not beconstant over time. There can be a preset target value of capture indexthat indicates the desired entrainment. This value can be in the rangeof 0.2 to 0.8 for example. In accordance with the known art of feedbackcontrol engineering, an embedded algorithm can compare the actualcapture index with the target 604 and increase stimulation energy if thecapture index is below target or reduce it if it is above it 605. Thestimulation energy can be adjusted by varying the delivered current,voltage, frequency or pulse duration. For example stimulation currentmay be increased or decreased in the range between 1 and 10 mA insuitable steps. Alternatively, stimulation pulse duration can beincreased or decreased in the range of 100 to 500 us in suitable steps,for example. A feedback control algorithm can be implemented in the IPGembedded software such as a PI or PID regulator known in the field ofcontrol engineering. In the embodiment used by inventors to gatherexperimental data, the stimulation current was manipulated in steps of0.1 to 0.5 mA to achieve the desired capture index.

FIG. 8 is a schematic view of a patient and therapy device in accordancewith embodiments of the invention. An implantable pulse generator 702 isprogrammed to generate stimulation pulse trains 703 at a fixed rate. Aright phrenic nerve of the patient 705 innervates the righthemidiaphragm 706. The stimulation pulse trains 703 are delivered to theright phrenic nerve 705 via the electrode lead 704.

Either the phrenic nerve of the hemidiaphragm itself could bestimulated. One or more electrodes could be placed on the diaphragm,adjacent the nerve (e.g., cuff electrode), intravenously proximate thenerve, or in any other location suitable to provide appropriatestimulation. The electrode(s) could be connected to an electrical pulsegenerator using leads or leadless technology. The pulse generator couldbe implanted within the patient or located externally.

The right phrenic nerve 705 conducts stimulation to the right hemidiaphragm 706, which responds with downward motion 707. The downwardmotion 707 of the diaphragm results in the inflation of the lungs andactivation of stretch receptors within the thoracic cavity. It isbelieved that periodic stretching generates periodic regular rhythm ofneural feedback inputs 708 to the brain 701. Respiratory neurons of thebrain are entrained by the neural input 708. The strength of stimulation703 elicits proportional response from the stimulated hemi-diaphragm706. The increased diaphragmic motion accordingly results in theincreased periodic regular neural input 708 to the brain 701.

When the signals reach necessary strength, respiratory entrainment ispresent and the desired fixed and repetitive coupling is establishedtemporarily between stimulation, mechanical inflation of the lungs andneural inspiratory activity in the respiratory control center of thebrain. Entrainment may occur at a 1:1 ratio (one mechanical inflation toone neural respiratory effort), but other integral ratios may be seen,as well as occasional aperiodic, chaotic behavior in the transitionbetween different integral ratio entrainment patterns. The 2:1 ratio oftwo stimulated inflations to one neural respiratory effort is seencommonly together with 1:1 ratio.

The brain responds to entrainment with the regular periodic sequence ofrespiratory drive 709 that is sent to respiratory muscles of thediaphragm via both right 705 and left 712 phrenic nerves as well as viathe airway control nerves 710 to the airway muscles resulting in thedesired dilation of the airway 711. The left hemi diaphragm 715 isinnervated by the left phrenic nerve 712 that is not stimulated by theIPG and therefore can on occasion exhibit independent behavior inresponse to the signals coming from the brain 701 and is not directlyaffected by the IPG 702. It is known that the muscle groups of right andleft hemi diaphragms are innervated separately by right and left phrenicnerves and move independently in response to signals from these nerves.The synchronized respiratory activity of the unstimulated hemi diaphragmis an indication of entrainment as opposed to pacing of respiration.

The IPG 702 can be equipped with additional leads 713 and means tomeasure respiration such as through transthoracic impedance sensing 714.Software embedded in the IPG programmable logic can respond to thechanges in respiration by adjusting the stimulation pulse train rhythm703. The respiratory sensing 714 can be also used by the IPG logic toset and change the rate of stimulation pulse trains 703 depending on thesensed intrinsic respiratory rate 709.

One skilled in the art will appreciate that the invention can bepracticed with embodiments other than those disclosed. The disclosedembodiments are presented for purposes of illustration and notlimitation, and the invention is limited only by the claims that follow.

1. A method comprising: a. defining a measured frequency zone based onmeasured physiological signals associated with the intrinsic contractionof a muscle; b. defining a stimulation frequency zone based onstimulation frequency of an electrical pulse generator configured tostimulate the muscle or a nerve associated with the muscle at adifferent frequency than the intrinsic frequency; c. stimulating themuscle or a nerve associated with the muscle; and d. determining theimpact of stimulation by comparing the measured power of an array ofsignals that fall within the measured frequency zone to the measuredpower of the array of signals that fall within the stimulation frequencyzone.
 2. The method of claim 1, wherein the physiological signal is asignal representative of respiration.
 3. The method of claim 2, whereinthe measured frequency zone comprises a range of frequencies proximatethe respiration frequency of a patient.
 4. The method of claim 1,wherein the muscle is a diaphragm muscle.
 5. A system for electricalstimulation of a nerve or muscle comprising; a. an electrical pulsegenerator that delivers energy to stimulate a muscle at a firstfrequency, the first frequency different from a second frequency atwhich the muscle intrinsically contracts; b. a sensor that sensesphysiologic activity indicative of contraction of the stimulated muscle;c. an electronic memory to store an array of data generated by thesensor over a period of time; d. a frequency analyzer that analyzes thearray of data to determine the power distribution across a frequencyband for the sensed physiologic activity; and e. circuitry to comparethe power in a band proximate the stimulation frequency to a total poweracross the frequency band for the sensed physiologic activity.
 6. Thesystem of claim 5, further comprising circuitry configured to increasethe energy delivered by the pulse generator if the ratio of the power inthe band proximate the stimulation frequency to the total power is belowa threshold.
 7. The system of claim 5, wherein the electrical pulsegenerator delivers the energy to stimulate the muscle by stimulating anerve associated with the muscle.
 8. A system for treating disorderedbreathing comprising; a. an electrical pulse generator capable ofproviding electrical stimulation signals to a phrenic nerve or diaphragmof a patient at a predetermined signal frequency; b. a respirationsensor capable of sensing a signal representative of the patient'srespiration; c. a frequency comparator that compares the power densityof the frequency distribution of sensed respiration signals over astimulation frequency band to the power density of sensed respirationsignals over a respiratory frequency band; and d. power adjustingcircuitry that adjusts the power of the electrical stimulation signalsprovided by the electrical pulse generation based on the comparison ofthe power densities.
 9. The system of claim 8, wherein the poweradjusting circuitry adjusts a stimulation current.
 10. The system ofclaim 8, wherein the power adjusting circuitry adjusts a stimulationvoltage.
 11. The system of claim 8, wherein the power adjustingcircuitry adjusts a frequency of the pulses in a pulse train.
 12. Thesystem of claim 8, wherein the power adjusting circuitry adjusts a pulseduration of the pulses in a pulse train.
 13. A method of treatingdisordered breathing comprising: a. detecting a signal representative ofthe respiration of a patient; b. conducting a frequency analysis of thesignal representative of respiration over a range of frequenciesconsistent with respiration; c. determining an intrinsic breathing rateor frequency; d. stimulating one hemidiaphragm of the patient at afrequency different from the intrinsic breathing frequency; e.conducting a frequency analysis of the respiration signal duringstimulation; f. dividing the power distribution in a frequency rangeproximate the stimulation frequency to the power of the range offrequencies consistent with respiration to determine a capture index;and g. modifying stimulation parameters based on the calculated captureindex.
 14. The method of claim 13, wherein the signal representative ofrespiration is transthoracic impedance.
 15. The method of claim 13,wherein the stimulation frequency is lower than the intrinsic breathingfrequency.
 16. The method of claim 13, wherein the stimulation power isincreased if the capture index is below a certain threshold.
 17. Themethod of claim 13, wherein the stimulation power is decreased if thecapture index is above a certain threshold.